May 20, 2020: Vol 20 No 66

COVID-19 has devastated certain countries, such as the UK and the USA. COVID-19 seems to have relatively spared other countries, including India, and it is unclear whether lockdown is the only reason for this.

In a very important study, Grifoni et al (2020) studied T cell response to COVID-19 infection in nonhospitalized COVID-19 convalescent patients (n=20) and in unexposed individuals (n=20). The median age of the convalescent patients was 44 years; the sample was 45% male, and most patients had only mild illness (with mostly cough, fatigue, and fever). The median age of the unexposed sample was 31 years; this sample was 35% male. Blood from the unexposed sample had been drawn between 2015 and 2018, when the sample could not possibly have been exposed to SARS-CoV-2. All subjects were resident in the USA.

Important findings were:

1. In COVID-19 convalescent patients, CD4+ and CD8+ T cells were identified that were specific to the SARS-CoV-2 virus that is responsible for the disease. CD4+ cells were identified in 100% of the patients, and CD8+ in nearly 70% of the patients.

2. The CD4+ response to the SARS-CoV-2 spike protein was robust and correlated with the magnitude of the IgG and IgA titers against the virus.

3. Besides targeting the spike protein, CD4+ cells also targeted M and N viral proteins, and several other viral proteins, as well, including nsp and ORF proteins.

4. CD8+ cells targeted spike, M, and several ORF SARS-CoV-2 proteins.

5. Astonishingly, about 40-60% of persons who were unexposed to SARS-CoV-2 had CD4+ cells that were reactive against different viral proteins. In these persons, whereas reactivity against the non-spike proteins reached statistical significance, that against the spike protein narrowly missed statistical significance.


In this study, COVID-19 convalescent patients showed a robust CD4+ and CD8+ T cell response against spike, M, N, and other SARS-CoV-2 viral proteins. Importantly, about half of the sample that was unexposed to the SARS-CoV-2 virus had CD4+ lymphocytes that were reactive against the virus, suggesting that there may be cross-tolerance between the common cold coronaviruses and SARS-CoV-2.


1. There are 4 coronaviruses that cause the common cold in humans: HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. Perhaps CD4+ cells against these viruses show cross-reactivity against SARS-CoV-2. This may explain why some persons and even some geographical areas seem to be relatively protected against COVID-19. Confirmation of this hypothesis would require study of T cell profiles in persons before exposure to SARS-CoV-2 and, again, after exposure to the virus. Such a study is not easily done!

2. Most of the COVID-19 vaccines under development target the spike protein with a view to amplify the CD4+ response against this protein. However, given that T cells in convalescent serum target other SARS-CoV-2 proteins, it may be desirable to include other antigens in the vaccine, as well.


Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, Rawlings SA et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 2020; epub ahead of print.


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